Project Summary/Abstract Upwards of 50 million individuals are afflicted by chronic pain in the US alone, with 3 million of these individuals suffering from neuropathic pain [1]. On a global scale, chronic pain affects ~1.5 billion individuals, with ~25% who endure lower back pain [2]. From a clinical perspective, the International Association for the Study of Pain approximates that 1 in 5 patients present with pain, and on an annual basis, 1 in 10 patients are typically identified as suffering from chronic pain [3]. Indeed, pain is the primary motivation for patients who seek medical attention [4]. The types of chronic pain reported are variable and may include back pain, headache, pelvic and musculoskeletal pain, with clearly higher incidences among laborers and geriatric patients [5]. Further, a continually increasing frequency of chronic pain stems from known causes including injuries, surgeries, cancer, and HIV/AIDS [6]. Approximately 25% of chronic pain arises from trauma and surgery, while moderate to severe pain is experienced by ~65% patients with advanced cancer or HIV/AIDS, and chronic non-cancer pain is reported by 70% of elderly patients [7]. On a global scale, the World Health Organization estimates that 80% of individuals do not receive sufficient treatment for severe pain [8]. A point of additional importance is that these chronic pain patients represent the primary end user of analgesics, which has largely been opiates. The societal consequence of the wide spread use of opiates has been profound and the need for alternative efficacious therapies is now appreciated at all levels. Chronic persistent post-operative pain (CPOP) is a devastating outcome from any type of surgical procedure. Its incidence is anywhere between 20-85% depending on the type of surgery, with thoracotomies showing one of the highest annual incidences of 30-60% [9]. Given that millions of patients (approximately 23 million yearly based on incidence) are affected by CPOP, the results are increased direct medical costs, increased indirect medical costs due to decreased productivity, and associated negative effects on an individual?s physical functioning, psychological state, and quality of life. Given these extensive public health and economic consequences there is a resurgence of research in the area of preventative analgesia. The highest incidence of CPOP is reported after limb amputations, thoracotomies, cardiac surgery, and breast surgery. Based on the current understanding, the criteria for CPOP has been as follows: 1. Pain that develops and increases in intensity after the surgical procedure; 2. The pain is 3-6 months of duration and affects quality of life; 3. The pain is continuation of acute post-surgical pain or develops after an asymptomatic period; 4. The pain is in the surgical field or follows a nerve distribution or dermatome that is near or within the surgical field; 5. Other causes of pain have been excluded. Given a high incidence of post-operative pain in post thoracotomy patients post lung cancer, we have focused our proposal on this patient population. The goal of this project is to evaluate a novel small molecule antagonist of MD2-TLR4, DT-001 in preclinical models of surgical pain representative of persistent post-operative pain. In collaboration with University of California, San Diego, DT-001 will be evaluated for its ability to block the development of neuropathic pain states. These studies will evaluate dose escalating efficacy of DT001 in rats in formalin and spinal nerve injury (SNI) models using both intrathecal and intravenous routes of administration. Tissues will be preserved to assess functional effects on relevant pain centers for analysis by Raft. With demonstration of efficacy, these studies will determine the optimal dose and route of administration of DT001 and guide a development path to IND and eventually clinical trials.